Streptococcus pneumonias is the most important bacterial pathogen causing Otitis Media, which is mainly characterized by mucin overproduction in the middle ear resulting in conductive hearing loss. However, the molecular mechanisms underlying S. pneumoniae-induced mucin overproduction in middle ear remain largely unknown. Our preliminary studies showed that NF-kappaB transcription factor is not required for mucin induction in response to S. pneumoniae. Interestingly, however, IKKalpha and IKKbeta, major upstream kinases for the activation of NF-kappaB transcription factors, appear to be involved in mucin gene transcription via a mechanism dependent on ERK MAP kinase signaling pathway, but independent of NF- kappaB transcription factor. These encouraging novel findings have thus led us to hypothesize that Gram- positive S. pneumoniae up-regulates MUC5AC mucin transcription via novel signaling networks involving IkappaB kinases-ERK signaling pathway in a NF-kappaB independent manner. This is accomplished by using molecular and cell biological approaches to fully understand the novel molecular mechanisms underlying S. pneumoniae-induced mucin gene transcription in middle ear, and this will lead to identifying potential therapeutic targets for inhibition of mucus overproduction in Otitis Media children. [unreadable] [unreadable] [unreadable]